Silenced tumor suppressor genes reactivated by DNA demethylation do not return to a fully euchromatic chromatin state
Silenced tumor suppressor genes reactivated by DNA demethylation do not return to a fully euchromatic chromatin state
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DOI：
10.1158/0008-5472.can-05-2481
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发表时间：
2006-04-01
期刊：
影响因子：
11.2
通讯作者：
Baylin, SB
中科院分区：
文献类型：
--
作者：
McGarvey, KM;Fahrner, JA;Baylin, SB
组蛋白H3赖氨酸9 （H3K9）和赖氨酸27 （H3K27）三甲基化是稳定沉默的异染色质的特性，而H3K9二甲基化（H3K9me2）对常染色质基因抑制很重要。在结直肠癌细胞中，当hMLH1启动子DNA高甲基化和异常沉默时，所有这些标记以及建立它们的关键酶都围绕在hMLH1启动子周围，但当基因未甲基化并在常染色质状态下完全表达时，这些标记不存在。当异常沉默的基因被DNA去甲基化并在5-aza-2'-脱氧胞苷处理后重新表达时，H3K9。和H3K9me2是唯一丢失的沉默标记。其他一系列沉默和DNA高甲基化的基因启动子即使在DNA甲基转移酶基因敲除后慢性DNA去甲基化和重新表达时也表现相同。我们的数据表明，当DNA高甲基化基因的转录在癌细胞中被激活时，它们的启动子保持在具有一定异色特征的环境中。这一发现对于重新激活异常沉默的癌症基因作为治疗策略的翻译目标具有重要意义。
Histone H3 lysine 9 (H3K9) and lysine 27 (H3K27) trimethylation are properties of stably silenced heterochromatin whereas H3K9 dimethylation (H3K9me2) is important for euchromatic gene repression. In colorectal cancer cells, all of these marks, as well as the key enzymes which establish them, surround the hMLH1 promoter when it is DNA hypermethylated and aberrantly silenced, but are absent when the gene is unmethylated and fully expressed in at euchromatic state. When the aberrantly silenced gene is DNA demethylated and reexpressed following 5-aza-2'-deoxycytidine treatment, H3K9. and H3K9me2 are the only silencing marks that, are lost. A series of other silenced and DNA hypermethylated gene promoters behave identically even when the genes are chronically DNA demethylated and reexpressed after genetic knockout of DNA methyltransferases. Our data indicate that,when transcription of DNA hypermethylated genes is activated in cancer cells, their promoters remain in an environment with certain heterochromatic characteristics. This finding has important implications for the translational goal of reactivating aberrantly silenced cancer genes as a therapeutic maneuver.